This invention relates to 3-substituted-4-oxoretionoic acids and 3,3-disubstituted-4-oxoretionoic acids and their esters.
In the discussion which follows, reference will be made to structures having the following formulas and sets of values: ##STR1##
It is known that administration of certain retinoids (compounds of the vitamin A group and their derivatives and analogues) may prevent or reduce carcinogen-induced neoplasia in epithelial tissues of animals, and that all-trans-retinoic acid (Structure Ia), 13-cis-retinoic acid (Structure IIa), and some of their derivatives and analogues exert a prophylactic effect on the development of pre-neoplastic and malignant epithelial lesions and may have a therapeutic effect on established cancers. Some examples of these effects in vivo are summarized by Moon et al. [Carcinogenesis, Vol. 3, No. 12, pages 1469-1472 (1982); Cancer Research (Supplement), Vol. 43, pages 2469s-2475s (1983); The Retinoids, Vol. 2, edited by M. B. Sporn, A. B. Roberts and D. S. Goodman, Academic Press, Inc., Orlando, Florida, 1984, pages 327-371]. Moreover, certain retinoids have demonstrated efficacy in the treatment of several human pre-malignancies and malignancies; see, for example, S. M. Lippman, J. F. Kessler, and F. L. Meyskens, Jr., Cancer Treatment Reports, Vol. 71, No. 5, pages 493-515, 1984. Furthermore, retinoids that induce differentiation of neoplastic cells or that potentiate immune responses may be useful in combination with cytotoxic anticancer drugs in the treatment of human cancers (e.g., Lotan and Nicholson, Biochemical Pharmacology, Vol. 37, No. 2, pages 149-154, 1988). Bioassays of new retinoids in organ-culture or cell-culture systems, in biochemical processes, and in animal models identify compounds that may be useful for preventing or treating pre-malignant, malignant, or other human conditions (e.g., Sporn and Roberts, The Retinoids, Vol. 1, edited by M. B. Sporn, A. B. Roberts and D. S. Goodman, Academic Press, Inc., Orlando, Fla., 1984, pages 235-279].
It has been shown that all-trans-4-oxoretinoic acid (Structure IIIa), also known as all-trans-4-ketoretinoic acid, is one of the metabolites of all-trans-retinoic acid (Ia) [Roberts and Frolik, Federation Proceedings, Vol. 38, No. 11, pages 2524-2527, 1979; Roberts et al., Archives of Biochemistry and Biophysics, Vol. 199, No. 2, pages 374-383, 1980; Frolik, The Retinoids Vol. 2, edited by M. B. Sporn, A. B. Roberts, and D. S. Goodman, Academic Press, Inc., Orlando, Fla. 1984, pages 177-208]. It has been postulated that 4-oxo-RA (IIIa) is a deactivation product of RA and a stage in the elimination of RA from the body [Roberts and Frolik, Roberts et al., Frolik; three citations above].